This proposal will investigate the role of small non-coding RNAs, termed microRNAs (miRs), in the regulation of sodium (Na+) transport in the distal kidney nephron. We will investigate the hypothesis that the mineralocorticoid hormone, aldosterone regulates the expression of specific miR clusters in the distal kidney nephron cortical collecting duct (CCD), to alter Na+ transport by targeting the expression of the scaffold protein intersectin-2. Using in vivo mouse models we will establish the regulation of miRs in the principal cells of the CCD. The significantly regulated miRs that are altered by aldosterone and other signaling pathways linked to sodium regulation will be determined. We will alter the expression of the miR-23~24~27 clusters to demonstrate its importance in maintaining sodium balance in the kidney. Finally the mechanism of intersectin-2 regulation of the epithelial sodium channel will be determined, to characterize the involvement of this novel aldosterone-repressed protein in Na+ regulation in the kidney.